Compositions and methods for transdermal oxybutynin therapy

ABSTRACT

The present invention provides compositions and methods for administering oxybutynin while minimizing the incidence and or severity of adverse drug experiences associated with oxybutynin therapy. In one aspect, these compositions and methods provide a lower plasma concentration of oxybutynin metabolites, such as N-desethyloxybutynin, which is presumed to be contributing at least in part to some of the adverse drug experiences, while maintaining sufficient oxybutynin plasma concentration to benefit a subject with oxybutynin therapy. The invention also provides isomers of oxybutynin and its metabolites that meet these characteristics of minimized incidence and/or severity of adverse drug experiences, and maintenance of beneficial and effective therapy for overactive bladder. In some aspects, the composition may be presented in the form of an unoccluded or free form topically administered gel.

PRIORITY

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 10/098,752, filed Mar. 15, 2002, which is acontinuation of U.S. patent application Ser. No. 09/559,711, filed Apr.26, 2000, each of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to compositions and methods forminimizing adverse drug experiences associated with oxybutynin therapy.Accordingly, this invention covers the fields of pharmaceuticalsciences, medicine and other health sciences.

BACKGROUND OF THE INVENTION

[0003] Oral oxybutynin therapy is currently used for treating variousforms of overactive bladder and urinary incontinence. Particularly,oxybutynin effectively treats neurogenically caused bladder disorders.Relief from such disorders is attributed to the anticholinergic andantispasmodic action which oxybutynin imparts to the parasympatheticnervous system and the urinary bladder detrusor muscle.

[0004] It is generally believed that, while this anticholinergicactivity contributes to oxybutynin's clinical usefulness, it alsocontributes to certain uncomfortable adverse drug experiences such asdry mouth, dizziness, blurred vision, and constipation. Morespecifically, these experiences have been generally attributed to thepresence and amount of active metabolites of oxybutynin, for example,N-desethyloxybutynin. The above-referenced adverse drug experiences areobserved in a majority of patients using current oxybutyninformulations. In some cases, these adverse experiences are severe enoughto persuade the patient to discontinue treatment.

[0005] In view of the foregoing, compositions and methods foradministering oxybutynin to help minimize the incidence and/or severityof the above-described adverse drug experiences are extremely desirable.

SUMMARY OF THE INVENTION

[0006] Accordingly, the present invention provides methods of minimizingan adverse drug experience associated with oxybutynin therapy whichcomprises the step of administering a pharmaceutical compositioncomprising oxybutynin to a subject such that the ratio of area under theplasma concentration-time curve (AUC) of oxybutynin to an oxybutyninmetabolite is about 0.5:1 to about 5:1. The adverse drug experience maybe any adverse experience resulting from administration of oxybutynin,for example, anticholinergic, and/or antimuscarinic in nature.

[0007] Specific examples of known oxybutynin adverse experiences includebut are not limited to: gastrointestinal/genitourinary experiences,nervous system experiences, cardiovascular experiences, dermatologicalexperiences, and opthalmic experiences, among others.

[0008] Oxybutynin has a chiral molecular center, leading to the presenceof (R)- and (S)-isomers. When metabolized, oxybutynin gives rise tometabolites such as N-desethyloxybutynin, which may also be present as(R)- and (S)-isomers or a combination thereof. The method of the presentinvention specifically encompasses each isomer for both oxybutynin andits any corresponding metabolites. For example, in one aspect, the meanplasma AUC ratio of (R)-oxybutynin to (S)-oxybutynin is about 0.7:1. Inanother aspect, the mean AUC ratio of (R)-N-desethyloxybutynin to(R)-oxybutynin is from about 0.4:1 to about 1.6:1. In one aspect, thismean AUC ratio may be about 1:1. In another aspect, the mean AUC ratioof (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is from about0.5:1 to about 1.3:1. For example, this mean AUC ratio may be about0.9:1. In another aspect, the metabolite may have a mean peak plasmaconcentration of less than about 8 ng/ml.

[0009] A pharmaceutical composition for administering oxybutynin to asubject is also provided, comprising oxybutynin that provides an AUCratio of oxybutynin to an oxybutynin metabolite of from about 0.5:1 toabout 5:1.

[0010] Delivery formulations useful in conjunction with the method ofthe present invention include but are not limited to: oral, parenteral,transdermal, inhalant, or implantable formulations. In one aspect of theinvention, the delivery formulation may be a transdermal deliveryformulation. In a more specific aspect, the delivery formulation may bea gel formulation that is topically administered to the skin in anunoccluded, or free form manner.

[0011] The composition of the present invention may include apharmaceutically acceptable carrier, and other ingredients as dictatedby the particular needs of the specific dosage formulation. Suchingredients are well known to those skilled in the art. See for example,Gennaro, A. Remington: The Science and Practice of Pharmacy 19^(th) ed.(1995), which is incorporated by reference in its entirety. For example,a transdermal formulation may include, but is not limited to, permeationenhancers, anti-irritants, adhesion adjusters, and combinations thereof.

[0012] In one aspect, the formulation of the present invention may be anoxybutynin gel formulation for topical application. Such a gel mayinclude a therapeutically effective amount of oxybutynin and a gelcarrier, wherein the formulation has a pH of from about 4 to about 11and wherein the oxybutynin is present as an oxybutynin free base, apharmaceutically acceptable oxybutynin salt, or a mixture thereof, andwherein the formulation is prepared for unoccluded topical applicationto a skin surface. In another aspect, the pH of the formulation may befrom about 4 to about 11. In a further aspect, the pH of the formulationmay be from about 5 to about 11. In yet a further aspect, the pH of theformulation may be from about 6 to about 11. In an additional aspect,the pH of the formulation may be from about 4 to about 10. In anotheraspect, the pH of the formulation can be from about 5 to about 10. In anadditional aspect, the pH of the formulation can be from about 6 toabout 10. In a more detailed aspect, the pH of the formulation may beabout 6. In yet another detailed aspect of the invention, the pH of theformulation is about 9.

[0013] According to another aspect of the invention, a gel formulationfor topical application is presented which includes a therapeuticallyeffective amount of oxybutynin in a gel carrier, which upon unoccludedtopical administration, is sufficient to provide an oxybutynin skinpermeation rate of at least about 10 ug/cm² over a period of at leastabout 24 hours.

[0014] In a further aspect of the invention, a gel formulation fortopical application is presented which includes a therapeuticallyeffective amount of oxybutynin in a gel carrier, which upon unoccludedtopical administration, is sufficient to achieve an oxybutynin plasmaconcentration of at least about 0.5 ng/ml within at least about 3 hoursafter initiation of administration.

[0015] In another aspect of the invention, a gel formulation is providedfor topical application that includes a therapeutically effective amountof oxybutynin in a gel carrier, which upon unoccluded topicaladministration, is sufficient to achieve an oxybutynin plasmaconcentration that is from about 0.5 to about 5 times an oxybutyninmetabolite plasma concentration.

[0016] In an additional aspect of the invention, a gel formulation fortopical application is provided that includes a therapeuticallyeffective amount of oxybutynin in a gel carrier, which upon unoccludedtopical administration, is sufficient to achieve a therapeuticallyeffective oxybutynin concentration and a maximum oxybutynin metaboliteplasma concentration of less than about 8 ng/ml.

[0017] In addition to the compositions recited herein, the presentinvention additionally encompasses a method for treating neurogenicbladder disorders in a subject which includes topically applying a gelformulation as recited herein to a skin surface of the subject.Moreover, the present invention includes a method of minimizing adverseside effects associated with oxybutynin therapy includes applying anoxybutynin gel formulation as recited herein to a skin surface asubject.

[0018] There has thus been outlined, rather broadly, the more importantfeatures of the invention so that the detailed description thereof thatfollows may be better understood, and so that the present contributionto the art may be better appreciated.

[0019] Other features of the present invention will become clearer fromthe following detailed description of the invention, taken with theaccompanying drawings and claims, or may be learned by the practice ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020]FIG. 1 is a graphical representation of total oxybutynin andN-desethyloxybutynin plasma concentrations measured following a 5 mgoxybutynin immediate-release oral dosage formulation.

[0021]FIG. 2 is a graphical representation of total oxybutynin andN-desethyloxybutynin plasma concentrations measured upon transdermaladministration according to the present invention, spanning a time frominitial oxybutynin administration to 24 hours therefrom.

[0022]FIG. 3 is a graphical representation of total oxybutynin andN-desethyloxybutynin plasma concentrations measured upon transdermaladministration according to the present invention, spanning a time frominitial oxybutynin administration to 96 hours therefrom, and for anadditional 12 hours following the removal of the transdermal system at96 hours.

[0023]FIG. 4 is a graphical representation of the results of treating asubject with overactive bladder with transdermal administration ofoxybutynin in accordance with the present invention, as compared totreatment with a 5 mg immediate-release oxybutynin oral tablet byrecording the number of episodes of urinary incontinence.

[0024]FIG. 5 is a graphical representation of the anticholinergicadverse experiences reported by subjects receiving treatment foroveractive bladder with a transdermal administration of oxybutynin inaccordance with the present invention, as compared to treatment with a 5mg oxybutynin immediate-release oral tablet.

[0025]FIG. 6 is a graphical representation of the plasma concentrationsproduced for the (R) and (S) isomers of both oxybutynin andN-desethyloxybutynin upon administering a 5 mg immediate-release oraltablet.

[0026]FIG. 7 is a graphical representation of the plasma concentrationsof (R) and (S) isomers for both oxybutynin and N-desethyloxybutyninachieved by transdermal administration in accordance with the presentinvention.

DETAILED DESCRIPTION

[0027] A. Definitions

[0028] In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set forthbelow.

[0029] The singular forms “a,” “an,” and, “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an adhesive” includes reference to one or more of suchadhesives, and reference to “an excipient” includes reference to one ormore of such excipients.

[0030] “Oxybutynin” refers to the compound having the general structureof:

[0031] The oxybutynin addition salt, oxybutynin HCl, is listed in theMerck Index, entry no. 7089, at page 1193, 12th ed., (1996, and is knownby several IUPAC names such as α-Cyclohexyl-hydroxy-benzenacetic acid4-(diethylamino)-2-butynyl ester hydrochloride;α-phenylcyclohexaneglycolic acid 4-(diethylamino)-2-butynyl esterhydrochloride; and 4-diethylamino-2-butynylphenylcyclohexylglycolatehydrochloride. “Oxybutynin” as used herein includes oxybutynin freebase, its acid addition salts such as oxybutynin HCl, their analogs andrelated compounds, isomers, polymorphs, and prodrugs thereof. It isgenerally known that oxybutynin may exist in one or both of its isomericforms, known as the (R)- and (S)-isomers, or a mixture of these twoisomers. These isomeric forms and their mixtures are within the scope ofthis invention. Notably, in some portions of the present application,the context may clearly dictate the specific form of oxybutynin, such asoxybutynin chloride, even though only “oxybutynin” is recited.

[0032] “Administration,” and “administering” refer to the manner inwhich a drug is presented to a subject. Administration can beaccomplished by various art-known routes such as oral, parenteral,transdermal, inhalation, implantation, etc. Thus, an oral administrationcan be achieved by swallowing, chewing, sucking of an oral dosage formcomprising the drug. Parenteral administration can be achieved byinjecting a drug composition intravenously, intra-arterially,intramuscularly, intrathecally, or subcutaneously, etc. Transdermaladministration can be accomplished by applying, pasting, rolling,attaching, pouring, pressing, rubbing, etc., of a transdermalpreparation onto a skin surface. These and additional methods ofadministration are well-known in the art.

[0033] The term “non-oral administration” represents any method ofadministration in which a drug composition is not provided in a solid orliquid oral dosage form, wherein such solid or liquid oral dosage formis traditionally intended to substantially release and or deliver thedrug in the gastrointestinal tract beyond the mouth and/or buccalcavity. Such solid dosage forms include conventional tablets, capsules,caplets, etc., which do not substantially release the drug in the mouthor in the oral cavity.

[0034] It is appreciated that many oral liquid dosage forms such assolutions, suspensions, emulsions, etc., and some oral solid dosageforms may release some of the drug in the mouth or in the oral cavityduring the swallowing of these formulations. However, due to their veryshort transit time through the mouth and the oral cavities, the releaseof drug from these formulations in the mouth or the oral cavity isconsidered deminimus or insubstantial. Thus, buccal patches, adhesivefilms, sublingual tablets, and lozenges that are designed to release thedrug in the mouth are non-oral compositions for the present purposes.

[0035] In addition, it is understood that the term “non-oral” includesparenteral, transdermal, inhalation, implant, and vaginal or rectalformulations and administrations. Further, implant formulations are tobe included in the term “non-oral,” regardless of the physical locationof implantation. Particularly, implantation formulations are known whichare specifically designed for implantation and retention in thegastrointestinal tract. Such implants are also considered to be non-oraldelivery formulations, and therefore are encompassed by the term“non-oral.”

[0036] The term “subject” refers to a mammal that may benefit from theadministration of a drug composition or method of this invention.Examples of subjects include humans, and other animals such as horses,pigs, cattle, dogs, cats, rabbits, and aquatic mammals.

[0037] As used herein, the terms “formulation” and “composition” areused interchangeably. The terms “drug” and “pharmaceutical” are alsoused interchangeably to refer to a pharmacologically active substance orcomposition. These terms of art are well-known in the pharmaceutical andmedicinal arts.

[0038] The term “transdermal” refers to the route of administration thatfacilitates transfer of a drug through a skin surface wherein atransdermal composition is administered to the skin surface.

[0039] The term “skin” or “skin surface” is meant to include not onlythe outer skin of a subject comprising one or more of epidermal layers,but also to include mucosal surfaces to which a drug composition may beadministered. Examples of mucosal surfaces include the mucosa of therespiratory (including nasal and pulmonary), oral (mouth and buccal),vaginal, and rectal cavities. Hence the terms “transdermal” mayencompass “transmucosal” as well.

[0040] The terms “enhancement”, or “permeation enhancement,” mean anincrease in the permeability of the skin, to a drug, so as to increasethe rate at which the drug permeates through the skin. Thus, “permeationenhancer” or simply “enhancer” refers to an agent, or mixture of agentsthat achieves such permeation enhancement.

[0041] An “effective amount” of an enhancer means an amount effective toincrease penetration of a drug through the skin, to a selected degree.Methods for assaying the characteristics of permeation enhancers arewell-known in the art. See, for example, Merritt et al., DiffusionApparatus for Skin Penetration, J. of Controlled Release 61 (1984),incorporated herein by reference in its entirety. By “effective amount”or “therapeutically effective amount,” or similar terms is meant anon-toxic but sufficient amount of a drug, to achieve therapeuticresults in treating a condition for which the drug is known to beeffective. The determination of an effective amount is well-within theordinary skill in the art of pharmaceutical and medical sciences. Seefor example, Curtis L. Meinert & Susan Tonascia, Clinical Trials:Design, Conduct, and Analysis, Monographs in Epidemiology andBiostatistics, vol. 8 (1986).

[0042] By the term “mean,” “mathematical mean,” “average,” or similarterms when used in conjunction with the recitation of a number, ornumbers, means the sum of all the individual observations or items of asample divided by the number of items in the sample.

[0043] By the term “matrix”, “matrix system”, or “matrix patch” is meanta composition comprising an effective amount of a drug dissolved ordispersed in a polymeric phase, which may also contain otheringredients, such as a permeation enhancer and other optionalingredients. This definition is meant to include embodiments whereinsuch polymeric phase is laminated to a pressure sensitive adhesive orused within an overlay adhesive.

[0044] A matrix system may also comprise an adhesive layer having animpermeable film backing attached onto the distal surface thereof and,before transdermal application, a release liner on the proximal surfaceof the adhesive. The film backing protects the polymeric phase of thematrix patch and prevents release of the drug and/or optionalingredients to the environment. The release liner functions similarly tothe impermeable backing, but is removed from the matrix patch prior toapplication of the patch to the skin as defined above. Matrix patcheswith the above-described general characteristics are known in the art oftransdermal delivery. See, for example, U.S. Pat. Nos. 5,985,317,5,783,208, 5,626,866, 5,227,169, which are incorporated by reference intheir entirety.

[0045] “Topical formulation” means a composition in which the drug maybe placed for direct application to a skin surface and from which aneffective amount of the drug is released. Such formulations may includegels, lotions, crèmes or other formulations which are applied to theskin. In some aspects, such formulations may be applied to the skin inan unoccluded form without additional backing, structures or devices.

[0046] As used herein, “unoccluded” and “non-occluded” may be usedinterchangeably, and refer to application of a topical formulation tothe skin without the use of a supporting or otherwise associatedstructure. In other words, the topical formulation is applied to theskin in a free form, which is sufficient to effect transdermal deliveryof oxybutynin without the use of structures, such as a backing member,etc.

[0047] As used herein, “gel” refers to a composition including acompound of high molecular weight which acts as a thickening agent toproduce a semisolid or suspension-type formulation. The thickening orgelling agents may be hydrophobic or hydrophilic and are generallypolymeric in nature. Gels which incorporate hydrophilic polymers aretypically known in the art as hydrogels. Gels may include a variety ofadditional components such as, but not limited to, active agents,excipients, solvents, emulsifiers, chelating agents, surfactants,emollients, permeation enhancers, preservatives, antioxidants,lubricants, pH adjusters, adjuvants, dyes, and perfumes.

[0048] “Adverse drug experience” refers to any adverse event associatedwith the use of a drug in a subject, including the following: an adverseevent occurring in the course of the use of a drug product inprofessional practice; an adverse event occurring from drug overdosewhether accidental or intentional; an adverse event occurring from drugabuse; an adverse event occurring from drug withdrawal; and any failureof expected pharmacological action. The adverse drug experience may leadto a substantial disruption of a person's ability to conduct normal lifefunctions. In some instances, the adverse drug experience may be seriousor life threatening.

[0049] While some of the adverse drug experiences may be expected, insome instances, such experiences may be unexpected. “Unexpected,” refersto an adverse drug experience that has not been previously catalogued bya responsible governmental agency (such as the Food and DrugAdministration of the United States) and or not provided in the currentlabeling for the drug product.

[0050] The unexpected adverse experiences may include events that may besymptomatically and pathophysiologically related to a known event, butdiffer from the event because of greater severity or specificity. Forexample, under this definition, hepatic necrosis would be unexpected (byvirtue of greater severity) if the known event is elevated hepaticenzymes or hepatitis. Similarly, cerebral thromboembolism and cerebralvasculitis would be unexpected (by virtue of greater specificity) if theknown event is cerebral vascular accidents. For a more comprehensivedefinition and description of adverse drug experience, see 21 C.F.R.§314.80, which is incorporated by reference in its entirety.

[0051] The majority of the adverse experiences associated withoxybutynin therapy may be categorized as anticholinergic, and/orantimuscarinic. Certain adverse experiences associated with oxybutyninhave been categorized in the Physician's Desk Reference ascardiovascular experiences, gastrointestinal/genitourinary experiences,dermatologic experiences, nervous system experiences, and opthalmicexperiences, among others.

[0052] Examples of cardiovascular adverse experiences include but arenot limited to: palpitations, tachycardia, vasodilation, andcombinations thereof. Examples of dermatologic adverse experiencesinclude but are not limited to: decreased sweating, rashes, andcombinations thereof. Examples of gastrointestinal/genitourinary adverseexperiences include but are not limited to: constipation, decreasedgastrointestinal motility, dry mouth, nausea, urinary hesitance andretention, and combinations thereof. Examples of nervous system adverseexperiences include but are not limited to: asthenia, dizziness,drowsiness, hallucinations, insomnia, restlessness, and combinationsthereof. Examples of opthalmic adverse experiences include but are notlimited to: amblyopia, cycloplegia, decreased lacrimation, mydriasis,and combinations thereof. Examples of other adverse experiences includebut are not limited to: impotence and suppression of lactation. A morecomprehensive listing of adverse experiences may be found in thelabeling of the oxybutynin formulations as provided by the regulatoryagencies.

[0053] The term “minimize” and its grammatical equivalents refer to areduction in the frequency and or severity of one or more adverse drugexperiences in a given subject or subject population. It is appreciatedthat the subject population may be of necessity much smaller in sizethan the general population that may be exposed to the drug and/or itsadverse experiences.

[0054] It is also appreciated that the results obtained from methods fordetermining the reduction in the frequency and/or severity of adversedrug experiences may be subject to variables such as intra-subject andinter-subject factors. However, it is also appreciated that certainscientifically accepted methods can be used to conduct the studies andthat the results from such studies are statistically reliable. Suchmethods and interpretation of the results from such methods arewell-known in the art. See, for example, Robert R. Sokal & F. JamesRohlf, Biometry: The Principles and Practice of Statistics in BiologicalResearch, 2^(nd) ed. (1969), which is incorporated by reference in itsentirety.

[0055] The phrase “area under the curve”, “area under the plasmaconcentration-time curve,” or similar terms are well known in thepharmaceutical arts. These values are calculated by plotting a graphwith data from plasma concentration of a given drug or its metabolitesas a function of time, with the X-axis generally representing time andthe Y-axis generally representing plasma concentration. The area underthe line formed by joining the various data points is then integratedinto a numerical value. See for example, Milo Gibaldi & Donald Perrier,PharmacoKinetics, 2^(nd) ed. (1982). The AUC multiplied by the clearanceor total body clearance (CL), of the substance being measured, thusprovides an estimate of the total amount, or dose, of the substancebeing measured (the drug or one or more of its metabolites). Plasmaconcentrations, AUC, and CL may be subject to inter- and intra-subjectvariation due to physiological and/or environment factors present inindividual subjects during the administration of medicinal agents, suchas oxybutynin, in various formulation and/or compositions. Therefore,individual and mean values may be subject to variability, however, thegeneral trends and relationships are preserved and reproducible.

[0056] Concentrations, amounts, solubilities, and other numerical datamay be presented herein in a range format. It is to be understood thatsuch range format is used merely for convenience and brevity and shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited.

[0057] For example, a concentration range of 0.1 to 5 ng/ml should beinterpreted to include not only the explicitly recited concentrationlimits of 0.1 ng/ml and 5 ng/ml, but also to include individualconcentrations such as 0.2 ng/ml, 0.7 ng/ml, 1.0 ng/ml, 2.2 ng/ml, 3.6ng/ml, 4.2 ng/ml, and sub-ranges such as 0.3-2.5 ng/ml, 1.8-3.2 ng/ml,2.6-4.9 ng/ml, etc. This interpretation should apply regardless of thebreadth of the range or the characteristic being described.

B. THE INVENTION

[0058] As described above, the present invention provides compositionsand methods for administering oxybutynin. These compositions and methodsare shown to have minimized the incidence and/or severity of an adverseexperience associated with oxybutynin administration, while providingsufficient oxybutynin to impart a therapeutic benefit. Without intendingto be bound to any specific theory, it is believed that the minimizationof adverse experiences is due in part to the reduction in plasmaconcentration of metabolites of oxybutynin such as N-desethyloxybutyninby the present compositions and methods when compared to conventionaloral administration. The phrase “conventional oral administration” ismeant to include the oral formulations as defined supra, and includesfor example, an immediate-release or sustained-release oral tabletcomprising oxybutynin. One such conventional oral formulation isavailable as a 5 mg immediate-release oral tablet.

[0059] 1) The Pharmacokinetic Aspects Associated with Total Drug andMetabolite Plasma Concentrations

[0060] The desired pharmacokinetic attributes such as reduced plasmaconcentrations of oxybutynin metabolites may be achieved by, interalia: 1) reducing the amount of oxybutynin administered, 2) reducing therate at which oxybutynin becomes available for metabolism by the body,and/or 3) avoiding or minimizing first-pass hepatic and/or intestinalmetabolism of oxybutynin. Using a non-oral route of administration isone way to achieve one or more of these objectives. Alternatively, anoral dosage form could be designed to mimic a non-oral administration toachieve the plasma concentrations and other pharmacokinetic datadescribed herein.

[0061] A clinical study has been performed to demonstrate one embodimentof the present invention. A cross-over clinical study in 16 healthyvolunteers was conducted to compare plasma concentrations andpharmacokinetics of oxybutynin and one of its metabolites,N-desethyloxybutynin, and their respective (R)- and (S)-enantiomericcomponents.

[0062] Conventional oral dosage forms of oxybutynin, such as the 5 mgoxybutynin tablet used in the present study produce significantly higherplasma concentrations of oxybutynin metabolites such asN-desethyloxybutynin as compared to the parent drug (See FIG. 1). Themean AUC ratio of metabolite to oxybutynin concentration is about 10:1in the majority of cases, and is generally greater than about 5:1.

[0063] In contrast, when oxybutynin is administered in a non-oral, slowrelease composition, such as the transdermal composition embodiment ofthe present invention, the mean AUC ratio of the metabolite(N-desethyloxybutynin) to oxybutynin is much lower. Generally, the meanAUC ratio of oxybutynin metabolite (N-desethyloxybutynin) to oxybutyninis less than about 2:1. Further, in the majority of instances, the ratiois less than about 1.2:1, and often, the ratio is approximately 0.9:1.(See FIG. 3).

[0064] Additionally, the mean N-desethyloxybutynin plasma concentrationis generally less than about 8 ng/ml, and in the majority of instancesis less than about 5 ng/ml. Often the mean is less than about 3 ng/ml.

[0065] 2) Pharmacokinetic Aspects of Isomers

[0066] The present inventors have investigated further into the aspectsdescribed above and have discovered that the present formulations andmethods provide significantly reduced levels of particular isomers ofcertain oxybutynin metabolites and that these reduced levels ofmetabolite isomers correlate to the minimized adverse drug experiencesdescribed above.

[0067] It is generally known that oxybutynin exists as an (R)- or as an(S)-isomer or a combination thereof. Particularly, (R)-oxybutynin hasbeen thought to be the more active of the two isomers, as indicated byanimal pharmacological studies using isolated tissues. See for example,Kachur J F, Peterson J S, Carter J P, et al. J. Pharm Exper. Ther. 1988;247:867-872; see also, Noronha-Blob L, Kachur J F. J. Pharm. Exper.Ther. 1990; 256:56-567. As such, (R)-N-desethyloxybutynin, being themore active constituent of the total amount of metabolite, maycontribute more significantly to adverse drug experiences such asanticholinergic adverse effects than the less active(S)-N-desethyloxybutynin. See for example, U.S. Pat. No. 5,677,346,which is incorporated by reference in its entirety.

[0068] Accordingly, plasma concentrations were measured for both (R)-and (S)-oxybutynin and the corresponding isomers of one of itsmetabolites, N-desethyloxybutynin during the clinical study mentionedabove. The tests performed revealed that the present invention resultsin significantly lower (R)-N-desethyloxybutynin plasma concentrationscompared to conventional oral dosage forms and administration methods.

[0069]FIG. 6 shows the plasma concentration profile from theconventional oxybutynin 5 mg oxybutynin oral tablet. As can be seen,(R)-N-desethyloxybutynin is present in the greatest concentration, andis several times the concentration of both (R)- and (S)-oxybutynin. Themean AUC ratio of the (R)-N-desethyloxybutynin to (R)-oxybutynin, thetwo most active isomers, following oral administration is about 17:1. Inaddition, the mean AUC ratio of (R)-N-desethyloxybutynin to(S)-N-desethyloxybutynin is about 1.5:1, and the mean AUC ratio of(R)-oxybutynin to (S)-oxybutynin is about 0.6:1. These ratios of AUCconsistently show that orally administered oxybutynin results in arelatively low amount of therapeutically active (R)-oxybutynin given thelarge total dose of racemic oxybutynin. Further, the oral dose resultsin a relatively large amount of (R)-N-desethyloxybutynin, the moietymost likely to be responsible for causing some or many of the adversedrug experiences.

[0070] In contrast, FIG. 7 shows the (R)- and (S)-isomer plasma profilesof the present invention which were achieved during the clinical studyby non-orally delivered oxybutynin. The mean AUC ratio of (R)-oxybutyninto (S)-oxybutynin is about 0.7:1, and the sustained plasmaconcentrations of (R)-oxybutynin are similar to the peak concentrationsobtained following oral administration. This comparable exposure to thetherapeutically active (R)-oxybutynin moiety is consistent with theinvention.

[0071] Thus, with transdermal administration, it has been discoveredthat: the mean AUC ratio of (R)-N-desethyloxybutynin to (R)-oxybutyninis lowered, resulting in greatly reduced amounts of the activemetabolites of oxybutynin, while providing a therapeutically effectiveamount of oxybutynin.

[0072] By comparing FIGS. 4, 5, and 7, it becomes clear that the presentcompositions and methods provide an optimal ratio of plasmaconcentrations of metabolites, such as (R)-N-desethyloxybutynin, tooxybutynin, such that these methods and compositions minimize adverseexperiences associated with oxybutynin administration, as compared totraditional oral formulations, while maintaining therapeuticallysufficient concentrations of (R)-oxybutynin to provide the benefits ofoxybutynin therapy. As indicated above, these compositions and methodsoffer a significant advancement in oxybutynin therapy.

[0073] 3) Therapeutic Aspects

[0074] A clinical study on the efficacy and minimization of incidenceand severity of adverse drug experiences associated with non-orallyadministered oxybutynin was conducted using 72 human subjects (patients)with overactive bladder. Approximately one-half of the patients wereadministered oxybutynin hydrochloride in an oral dosage formulation. Theremaining patients were administered oxybutynin using a non-oral routeof delivery such as a transdermal adhesive matrix patch over a period ofabout 6 weeks. The results are displayed graphically in FIGS. 4 and 5.

[0075] The non-oral, sustained-release composition of this invention wascompared for its therapeutic efficacy with the conventional 5 mg oraltablet of oxybutynin. The mean number of incontinent episodesexperienced per day as derived from a multiple-day patient urinary diarywas used as the desired therapeutic efficacy indicator. The data showthat the number of incontinent episodes for those individuals treated bythe non-oral method of the present invention is nearly identical to thenumber for those treated with the oral formulation. (See FIG. 4).

[0076] Next, the non-oral sustained-release formulation of the presentinvention was compared to the conventional immediate-release oral tabletfor the incidence and severity of adverse drug experiences. The adverseexperience of dry mouth was selected as an indicator for thisexperiment. As can be seen, only 6% of the participants who received theconventional oral oxybutynin tablet reported no dry mouth effects.Conversely, 94% of these participants reported experiencing some drymouth.

[0077] In contrast, 62% of the participants who were treated with thetransdermal adhesive matrix patch of the present invention reported nodry mouth effects. Therefore, only 38% of these participants reportedexperiencing some dry mouth, and none rated the dry mouth asintolerable.

[0078] These data show that the adverse experiences associated withoxybutynin administration can be minimized significantly, while fullyretaining the therapeutic efficacy of oxybutynin by administeringoxybutynin such that an optimal ratio of AUC of oxybutynin metabolite tooxybutynin results.

[0079] 4) Summary of Pharmacokinetic Aspects of the Invention

[0080] From the above-described pharmacokinetic data, the followingaspects of the invention can be presented. In one aspect, the mean peakplasma concentration of an oxybutynin metabolite is less than about 8ng/ml. In another aspect, the mean peak plasma concentration of themetabolite is from about 0.5 ng/ml to about 8 ng/ml; in yet anotheraspect, the concentration is less than about 5 ng/ml; in yet anotheraspect, the concentration is from about 1.0 ng/ml to about 3 ng/ml. Insome aspects, the metabolite of oxybutynin is N-desethyloxybutynin.

[0081] In some aspects, the mean oxybutynin metabolite AUC is reduced toan amount which does not exceed the oxybutynin AUC by more than a ratioof about 2:1. In some aspects, the mean oxybutynin metabolite AUC isreduced to less than about 0.9:1 ng/ml.

[0082] In some aspects, the present invention provides compositions andmethods for administering oxybutynin to a subject such that the mean AUCratio of oxybutynin to an oxybutynin metabolite is about 0.5:1 to about5:1. In some aspects, the ratio is from about 0.5:1 to about 4:1; insome other aspects, the ratio is from about 1:1 to 5:1; in yet otheraspects, the ratio is from about 0.8:1 to about 2.5:1; in yet some otheraspects, the ratio is from about 0.8:1 to about 1.5:1. In all the aboveaspects, the metabolite may be N-desethyloxybutynin.

[0083] Another way of characterizing the method of the present inventionis by specifying particular plasma concentrations for oxybutynin andmetabolite concentrations at certain time intervals following treatmentinitiation. Therefore, in one aspect, oxybutynin plasma concentrationsare below about 2.0 ng/ml at about 6 hours after oxybutynin treatmentinitiation. In another aspect, the metabolite plasma concentrations arealso below about 2.0 ng/ml at about 6 hours after treatment initiation.

[0084] In yet another aspect, oxybutynin and its metabolite plasmaconcentrations are below about 8 ng/ml at about 24 hours after initialoxybutynin administration. Further, mean steady state oxybutynin and itsmetabolite plasma-concentrations are below about 8 ng/ml for theduration of oxybutynin treatment.

[0085] In one aspect, the mean peak and mean AUC for(R)-N-desethyloxybutynin are about equal to or less than the mean peak,and mean AUC for (S)-N-desethyloxybutynin. In another aspect, the meanAUC ratio of (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin isabout 0.9:1. In yet another aspect, the mean peak and mean AUC for(R)-oxybutynin are approximately equal to (R)-N-desethyloxybutynin. Inanother aspect, the ratio of (R)-N-desethyloxybutynin to(S)-N-desethyloxybutynin is about 1:1.

[0086] In an additional aspect, (R)-N-desethyloxybutynin has a mean peakplasma concentration of less than about 4 ng/mL. In another aspect,(R)-N-desethyloxybutynin has a mean peak plasma concentration betweenabout 0.25 to about 4 nm/ml, and about 1.5 ng/ml.

[0087] In a one aspect, (R)-N-desethyloxybutynin has a mean AUC of about100 ng×hr/ml. In another aspect, (R)-N-desethyloxybutynin has a mean AUCfrom about 30 ng×hr/ml to about 170 ng×hr/ml.

[0088] In yet another aspect, the plasma concentration of(R)-N-desethyloxybutynin is below about 1 ng/ml at about 6 hours afterinitiation of oxybutynin administration. In a further aspect, the plasmaconcentration of (R)-N-desethyloxybutynin is below about 2 ng/ml atabout 24 hours after initiation of oxybutynin administration.

[0089] Therapeutic oxybutynin plasma concentrations vary based on theseverity of incontinence. Generally, therapeutic results may be obtainedfrom oxybutynin plasma concentrations as low as 0.5 ng/ml. Therapeuticblood levels may be achieved using the method of the present inventionin as little as 3 hours after treatment initiation, with peak oxybutyninplasma concentrations being reached in about 24 hours. However, thesegeneral parameters are not limitations on the way in which the desiredplasma levels may be achieved. Different delivery methods, rates, andamounts may be used to effect the desired plasma concentrations byemploying a formulation which produces different parameters.

[0090] 5) Composition Aspects

[0091] Any pharmaceutically acceptable compositions and methods foradministering such compositions may be used for achieving the desiredaspects of this invention. For example, oral and non-oral compositionsand methods of administration can be used. Non-oral compositions andmethods of administration include parenteral, implantation, inhalation,and transdermal compositions and methods.

[0092] Oral compositions and administrations can comprise ofslow-release compositions that are designed to mimic the non-oralcompositions and administrations that are specifically disclosed hereinin terms of their pharmacokinetic attributes described above. One ofordinary skill in the art would readily understand how to formulate andadminister such slow-release oral formulations. These formulations cantake the form of a tablet, capsule, caplet, pellets, encapsulatedpellets, etc., or a liquid formulation such as a solution or suspension.See, for example, U.S. Pat. No. 5,840,754, and WO 99/48494 which areincorporated by reference in their entirety.

[0093] Parenteral compositions and administrations may includeintravenous, intra-arterial, intramuscular, intrathecal, subcutaneous,etc. These compositions can be prepared and administered to provideslow-release of oxybutynin to achieve the pharmacokinetic profile andtherapeutic benefits described above. One specific example of preparinga depot-formulation for parenteral use is provided herein. Generalmethods for preparing sustained delivery of drugs for parenteral usecomprising microspheres are known in the art. See for example, U.S. Pat.Nos. 5,575,987, 5,759,583, 5,028,430, 4,959,217, and 4,652,441, whichare incorporated by reference in their entirety.

[0094] Implantation is a technique that is well-established to providecontrolled release of drugs over a long period of time. Severalsubcutaneously implantable devices have been disclosed in the art. Seefor example, U.S. Pat. Nos. 5,985,305, 5,972,369, and 5,922,342, whichare incorporated by reference in their entirety. By employing thesegeneral techniques, one of ordinary skill in the art can prepare andadminister implantable oxybutynin compositions to achieve thepharmacokinetic and therapeutic benefits of this invention.

[0095] Examples of oxybutynin transdermal administration formulationsinclude but are not limited to: 1) topical formulations such asointments, lotions, gels, pastes, mousses, aerosols, and skin creams; 2)transdermal patches such as adhesive matrix patches and liquid reservoirsystems. Other non-oral examples include transmucosal tablets such asbuccal, or sublingual tablets or lozenges, and suppositories.

[0096] In addition to the desired amount of oxybutynin, transdermaloxybutynin formulations may also include a permeation enhancer, ormixture of permeation enhancers in order to increase the permeability ofthe skin to oxybutynin. An index of permeation enhancers is disclosed byDavid W. Osborne and Jill J. Henke, in their publication entitled SkinPenetration Enhancers Cited in the Technical Literature, published in“Pharmaceutical Technology” (June 1998), which may also be found at theworldwide web address known as:pharmtech.com/technical/osborne/osborne.htm, which is incorporated byreference herein.

[0097] More particularly, permeation enhancers known to enhance thedelivery of oxybutynin include but are not limited to: fatty acids,fatty acid esters, fatty alcohols, fatty acid esters of lactic acid orglycolic acid, glycerol tri-, di- and monoesters, triacetin, short chainalcohols, and mixtures thereof. Specific species or combinations ofspecies may be selected from the above listed classes of compounds byone skilled in the art, in order to optimize enhancement of theparticular oxybutynin composition employed.

[0098] The transdermal formulation of the present invention may take theform of a non-occlusive topical formulation, such as a gel, ointmentsuch as a lotion, cream or paste, or an occlusive device such as atransdermal patch. A transdermal patch in accordance with the presentinvention may either be an adhesive matrix patch, a liquid reservoirsystem type patch, a buccal tablet, or the like. Optional ingredientssuch as adhesives, excipients, backing films, etc, and the requiredamount of each will vary greatly depending upon the type of patchdesired, and may be determined as needed by one ordinarily skilled inthe art. Methods for preparing and administering the transdermalformulations with the above-described characteristics are known in theart. See, for example, U.S. Pat. Nos. 5,762,953, and 5,152,997, whichare incorporated by reference in their entirety.

[0099] In one aspect of the present invention, a free form oxybutyninointment may be prepared for topical administration in accordance withthe discussion herein. An ointment is a semisolid pharmaceuticalpreparation based on a well known materials such as an oleaginous base,lanolin, emulsions, or water-soluble bases. Preparation of ointments iswell known in the art such as described in Remington, supra, vol. 2, pp.1585-1591. Such preparations often contain petrolatum or zinc oxidetogether with an active agent. Oleaginous ointment bases suitable foruse in the present invention include generally, but are not limited to,vegetable oils, animal fats, and semisolid hydrocarbons obtained frompetroleum. Absorbent ointment bases of the present invention may containlittle or no water and may include components such as, but not limitedto, hydroxystearin sulfate, anhydrous lanolin and hydrophilicpetrolatum. Emulsion ointment bases of the present invention are eitherwater-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and mayinclude, but are not limited to, cetyl alcohol, glyceryl monostearate,lanolin, polyalkylsiloxanes, and stearic acid. Water-soluble ointmentbases suitable for use in the present invention may be prepared frompolyethylene glycols of varying molecular weight.

[0100] In an additional aspect, ointments of the present invention mayinclude additional components such as, but not limited to, additionalactive agents, excipients, solvents, emulsifiers, chelating agents,surfactants, emollients, permeation enhancers, preservatives,antioxidants, lubricants, pH adjusters, adjuvants, dyes, and perfumes.The specific choice and compositions of such additional components maybe made by those skilled in the art in accordance with the principles ofthe present invention.

[0101] In another aspect of the present invention, a free formoxybutynin cream may be prepared in accordance with the principles ofthe present invention. Creams are a type of ointment which are viscousliquids or semisolid emulsions, either oil-in-water or water-in-oil, asis well known in the art. Cream bases may be soluble in water, andcontain an oil phase, an emulsifier, an aqueous phase, and the activeagent. In a detailed aspect of the present invention, the oil phase maybe comprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol. In another detailed aspect of the present invention, theaqueous phase may exceed the oil phase in volume, and may contain ahumectant. In another detailed aspect of the present invention, theemulsifier in a cream formulation may be a nonionic, anionic, cationicor amphoteric surfactant.

[0102] In a more detailed aspect of the present invention, the free formoxybutynin cream is an oil-in-water emulsion. The water phase of theoxybutynin cream may contain between about 20 and about 60% w/w ofwater, between about 1 and about 15% w/w of at least one emulsifier, upto about 50% w/w of an oil phase, and up to about 1% w/w of apreservative such as a paraben. The oil phase of the free formoxybutynin cream may contain up to about 40% w/w of a solvent, up toabout 15% w/w of at least one emulsifier, up to about 40% w/w of an oilphase, and up to about 1% w/w of a preservative such as a paraben.

[0103] In another aspect of the present invention, a free formoxybutynin lotion may be prepared in accordance with the principles ofthe present invention. A lotion is an ointment which may be a liquid orsemi-liquid preparation in which solid particles, including the activeagent, are present in a water or alcohol base. Lotions suitable for usein the present invention may be a suspension of solids or may be anoil-in-water emulsion. In another aspect of the present invention,lotions may also contain suspending agents which improve dispersions orother compounds which improve contact of the active agent with the skin,e.g., methylcellulose, sodium carboxymethylcellulose, or similarcompounds.

[0104] In an additional aspect, oxybutynin lotions of the presentinvention may include additional components such as, but not limited to,additional active agents, excipients, solvents, emulsifiers, chelatingagents, surfactants, emollients, permeation enhancers, preservatives,antioxidants, lubricants, pH adjusters, adjuvants, dyes, and perfumes.The specific choice and compositions of such additional components maybe made by those skilled in the art in accordance with the principles ofthe present invention and may differ from the components which would bechosen for other topical formulations of the present invention.

[0105] In another more detailed aspect of the present invention, freeform oxybutynin lotions may be an emulsion of a water and oil phase. Thewater phase of the oxybutynin lotion may contain between about 20% w/wand about 90% w/w of an excipient such as water, up to about 5% w/w of asurfactant, up to about 5% w/w of sodium chloride or the like, and up toabout 1% w/w of a preservative such as a paraben. The oil phase of theoxybutynin lotion may contain up to about 40% w/w of at least onesolvent such as glycerin and cetyl alcohol, up to about 10% w/w of anabsorbent base such as petrolatum, up to about 5% w/w of an antioxidantsuch as isopropyl palmitate, up to about 5% w/w of an oil phase such asdimethicone, and up to about 1% w/w of a preservative such as a paraben.

[0106] In yet another aspect of the present invention, a free formoxybutynin paste may be prepared in accordance with the presentinvention. Pastes of the present invention are ointments in which thereare significant amounts of solids which form a semisolid formulation inwhich the active agent is suspended in a suitable base. In a detailedaspect of the present invention, pastes may be formed of bases toproduce fatty pastes or made from a single-phase aqueous gel. Fattypastes suitable for use in the present invention may be formed of a basesuch as petrolatum, hydrophilic petrolatum or the like. Pastes made fromsingle-phase aqueous gels suitable for use in the present invention mayincorporate cellulose based polymers such as carboxymethylcellulose orthe like as a base.

[0107] In an additional aspect, oxybutynin pastes of the presentinvention may include additional components such as, but not limited to,additional active agents, excipients, solvents, emulsifiers, chelatingagents, surfactants, emollients, permeation enhancers, preservatives,antioxidants, lubricants, pH adjusters, adjuvants, dyes, and perfumes.

[0108] In another aspect of the present invention, a free formoxybutynin gel may be prepared. An oxybutynin gel prepared in accordancewith the present invention may be a preparation of a colloid in which adisperse phase has combined with a continuous phase to produce a viscousproduct. The gelling agent may form submicroscopic crystalline particlegroups that retain the solvent in the interstices. As will beappreciated by those working in art, gels are semisolid, suspension-typesystems. Single-phase gels can contain organic macromoleculesdistributed substantially uniformly throughout a carrier liquid, whichmay be aqueous or non-aqueous and may contain an alcohol or oil.

[0109] In another aspect, the transdermal formulation of the presentinvention may be a topical gel containing oxybutynin for unoccludedadministration to the skin. A variety of specific gel vehicles are knownto those of ordinary skill in the art. Examples of specific gel types,their manufacture and use may be found, for example, in U.S. Pat. Nos.2,909,462; 4,340,706; 4,652,441; 5,516,808; 5,643,584; 5,840,338;5,912,009; and 6,258,830, each of which are incorporated herein byreference in their entirety.

[0110] However, in some aspects, the gel formulation may be prepared byproviding a gelling agent, usually in a powdered form, and adding anexcipient such as water in the case of a hydrophilic gelling agent ormineral oil in the case of a hydrophobic gelling agent. The gel thenswells and may be optionally neutralized. In a separate vessel,oxybutynin may be dissolved in an appropriate solvent. The dissolvedoxybutynin and the gel may then be mixed to form the final gelformulation. Other methods of producing a drug-containing gel will berecognized by those of ordinary skill in the art.

[0111] Although gels used in reservoir devices may have similarcomponents additional considerations may be important in designing afree form gel. For example, free form gels may offer a number ofadvantages, such as ease of administration, increased patientcompliance, simple adjustment of dosage, decreased manufacturing costs,and reduced skin irritation. Moreover, certain excipients useful ineffecting administration of oxybutynin may be included in a free formgel in greater amounts, than is possible in an occluded gel, such as inan LRS patch, due to performance factors such as skin irritation, etc.

[0112] In accordance with a more detailed aspect of the presentinvention, the free form gel may include a variety of additionalcomponents such as, but not limited to, additional active agents,excipients, solvents, emulsifiers, chelating agents, surfactants,emollients, permeation enhancers, preservatives, antioxidants,lubricants, pH adjusters, adjuvants, dyes, and perfumes. The additionalcomponents may be added to the dissolved oxybutynin either before orafter combination with the gel. Further, in order to prepare a uniformgel, dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing orstirring, or combinations thereof. It will be recognized, however, bythose skilled in the art that other methods and means of incorporatingthe oxybutynin and other components into the gel may be employedconsistent with the teachings of the present invention.

[0113] In accordance with the present invention, the free form gel maybe aqueous or non-aqueous based. In either case, the formulation shouldbe designed to deliver the oxybutynin in accordance with the releaserates and blood plasma concentrations recited herein. In one aspect ofthe present invention, aqueous gels may comprise water or water/ethanoland about 1-5 wt % of a gelling agent. In another aspect of the presentinvention, non-aqueous gels may be comprised of silicone fluid, such ascolloidal silicon dioxide, or mineral oil. The suitability of aparticular gel depends upon the compatibility of its constituents withboth the oxybutynin and the permeation enhancer, if used, and any othercomponents in the formulation.

[0114] In accordance with the present invention, oxybutynin used in thefree form gel may be provided as the oxybutynin free base, its acidaddition salts such as oxybutynin HCl, their analogs and relatedcompounds, isomers, polymorphs, prodrugs, optically pure (R) or (S)isomers, racemic mixture and combinations thereof. The oxybutynin may beprovided in a micronized form or other powdered form. In one aspect ofthe present invention, the oxybutynin is present at about 0.1 wt % toabout 10 wt % of the free form gel. In accordance with one aspect of thepresent invention, the oxybutynin may be present between about 5 andabout 20 mg/gram.

[0115] In accordance with the present invention, the gelling agent maybe a compound of high molecular weight which acts as a thickening agentto produce a semisolid or suspension-type formulation. As mentionedabove, gelling agents may be hydrophobic or hydrophilic and aregenerally polymers. Gels which incorporate hydrophilic polymers arereferred to as hydrogels, as is understood by those skilled in the art.

[0116] Examples of suitable gelling agents for use in the presentinvention may include synthetic polymers such as, but not limited to,polyacrylic acids or poly(1-carboxyethylene), carboxypolymethylenesprepared from acrylic acid cross-linked with allyl ethers of(polyalkyl)sucrose or pentaerythritol (e.g. CARBOPOL940/941/980/981/1342/1382 and carbamer polymers such as carbomer934P/974P), sodium acrylate polymers (e.g. AQUAKEEP J-550/J-400), otherpolycarboxylic acids, alkyl acrylate polymers (e.g. PEMULEN), andmixtures or copolymers thereof. In another aspect of the presentinvention, the gelling agent is a CARBOPOL. In one more detailed aspectof the present invention, the gelling agent is an alkyl acrylatepolymer. In yet another aspect of the present invention, the gellingagent is a mixture of CARBOPOL and an alkyl acrylate polymer.

[0117] In another aspect of the present invention, suitable gellingagents may include vinyl polymers such as but not limited tocarboxyvinyl polymers, polyvinyl pyrrolidone, polyvinyl alcohol,polyvinyl methyl ether, polyvinyl ether, polyvinyl sulfonates, andmixtures or copolymers thereof.

[0118] In a further aspect of the present invention, suitable gellingagents may include polymers such as but not limited to polyethylenecompounds (e.g. polyethylene glycol, etc.), polysaccharides (e.g.polysucrose, polyglucose, polylactose, etc.) and salts thereof, acrylicacid esters, alkoxybutyninpolymers (e.g.polyoxyethylene-polyoxypropylene copolyiners such as the PLURONIC lineof BASF, Parsippany, N.J.), polyethylene oxide polymers, polyethers,gelatin succinate, colloidal magnesium aluminum silicate (which may beuseful as a gel stabilizer in conjunction with another gelling agent),petroleum jelly and mixtures of copolymers thereof.

[0119] Suitable gelling agents also include cellulose polymers such ashydroxypropyl cellulose (e.g. KLUCEL), hydroxypropylmethyl cellulose(e.g. KLUCEL HF, METHOCEL), hydroxypropylethyl cellulose,hydroxypropylbutyl cellulose, hydroxypropylpentyl cellulose,hydroxyethyl cellulose (NATROSOL), ethylcellulose, carboxymethylcellulose, hydroxypropylmethyl cellulose phthalate, and celluloseacetate. In one more detailed aspect of the present invention, thegelling agent is hydroxypropyl cellulose. In a more detailed aspect ofthe present invention, the gelling agent is hydroxyethyl cellulose. Inyet another aspect of the present invention, the gelling agent is amixture of hydroxyethyl cellulose and an alkyl acrylate polymer. In afurther aspect of the present invention, the gelling agent is a mixtureof hydroxypropyl cellulose and a CARBOPOL.

[0120] In yet another more detailed aspect of the present invention,suitable gelling agents may be natural gelling agents include, dextran,gaur-gum, tragacanth, xanthan gum, sodium alginate, sodium pectinate,sodium alginate, acacia gum, Irish moss, karaya gum, guaiac gum, locustbean gum, etc., while natural high molecular weight compounds include,among others, various proteins such as casein, gelatin, collagen,albumin (e.g. human serum albumin), globulin, fibrin, etc. and variouscarbohydrates such as cellulose, dextrin, pectin, starches, agar,mannan, and the like. These substances may be also be chemicallymodified, e.g. esterified or etherified forms, hydrolyzed forms (e.g.sodium alginate, sodium pectinate, etc.) or salts thereof.

[0121] The amount of gelling agent employed in a gel of the presentinvention may vary depending on the specific result to be achieved.However, in one aspect, the amount of gelling agent may be from about0.05 to about 10 wt % of the gel formulation. In a more detailed aspect,the amount of gelling agent may be 0.1 to 5 wt % of the gel formulationprior to introduction of the dissolved oxybutynin and any accompanyingcomponents. In yet a more detailed aspect, the free form gel may containabout 0.1 to about 3 wt % of a gelling agent in the gel formulation.

[0122] In another aspect of the present invention, solvents orsolubilizing agents may also be used in the free form gel. Such solventsmay be necessary when the drug is not soluble in the chosen gellingagent. Suitable solvents for use in the present invention include, butare not limited to lower alcohols, ethanol, isopropanol, benzyl alcohol,propanol, methanol, other C₄-C₁₀ mono-alcohols and mixtures thereof. Inanother aspect the solvents suitable for use in the present inventionmay include albumin, gelatin, citric acid, ethylenediamine sodiumtetraacetate, dextrin, DMSO, dimethylformamide, 2-pyrrolidone,N-(2-hydroxyethyl) pyrrolidone, N-methyl pyrrolidone,1-dodecylazacycloheptan-2-one and othern-substituted-alkyl-azacycloalkyl-2-ones (azones), sodium hydrosulfiteand mixtures thereof.

[0123] In one aspect, the ethanol may be present from about 60% to about85% w/w of the formulation. In another aspect, the ethanol may bepresent from about 65% to about 80% w/w of the formulation. In anotheraspect, the ethanol may be present from about 70% to about 85% w/w ofthe formulation. In another aspect, the ethanol may be present fromabout 70% to about 75% w/w of the formulation.

[0124] In one aspect, the water may be present from about 1% to about30% w/w of the formulation. In another aspect, the water may be presentfrom about 5% to about 30% w/w of the formulation. In another aspect,the water may be present from about 5% to about 20% w/w of theformulation. In yet another aspect, the water may be present from about10% to about 30% w/w of the formulation. In another aspect, the watermay be present from about 10 to about 25% w/w of the formulation. In yetanother aspect, the water may be present from about 10% to about 20% w/wof the formulation. In yet another aspect, the water may be present fromabout 15% to about 25% w/w of the formulation. In another aspect, thewater may be present from about 20% to about 25% w/w of the formulation.

[0125] Those of ordinary skill in the art will appreciate that thespecific amount and type of solvent selected may be determined based ona specific result to be achieved. However, in one aspect, the amount ofsolvent may be at least about 25% w/w of the formulation. In anotheraspect, the amount of solvent may be at least about 30% w/w of theformulation. In a further aspect, the amount of solvent may be at leastabout 40% w/w of the formulation. In an additional aspect, the amount ofsolvent may be at least about 70% w/w of the formulation.

[0126] In yet a more detailed aspect of the present invention,excipients such as, but not limited to, water, mineral oils, or siliconfluids may also be added and are largely dependent on the chosen gellingagent. The excipient may comprise a substantial portion of the gelformulation, i.e. greater than about 50%. In one aspect of the presentinvention, the free form gel contains excipient in an amount from 0% toabout 75%

[0127] In yet another more detailed aspect of the present invention, anemulsifier may also be used particularly when solvent is used.Emulsifiers suitable for use in the present invention include, but arenot limited to, polyols and esters thereof such as glycols, propyleneglycol, polyethylene glycol, glycolhexylene glycol, ethylene glycol,glycerol, butanediol, polyethylene glycol monolaurate, and propyleneglycol ester of alginic acid. Emulsification may be accomplished byconventional dispersion techniques. For example, intermittent shaking,mixing by means of a propeller mixer, turbine mixer or the like, colloidmill operation, mechanical homogenization, ultrasonication, or otherknown methods may be utilized. Emulsifiers may form stable oil-in-wateremulsion, and such emulsifiers are exemplified by anionic surfactants(e.g. sodium oleate, sodium stearate, sodium laurylsulfate, etc.),nonionic surfactants (e.g. polyoxyethylene sorbitan fatty acid esters(Tween 80 and Tween 60, Atlas Powder, U.S.A.), polyoxyethylene castoroil derivatives (HCO-60 and HCO-50, Nikko Chemicals, Japan], etc.),polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethylcellulose,lecithin, gelatin, and combinations thereof. The concentration of theemulsifier may be selected from the range of about 0.01% to about 20%.It will be noted that many of these emulsifiers also act as gellingagents.

[0128] In another aspect of the present invention, a chelating agent maybe used to prevent precipitation or decomposition of the oxybutynin.Suitable chelating agents for use in the present invention may include,but are not limited to, sodium and calcium salts of EDTA, and edetatedisodium.

[0129] In yet a more detailed aspect of the present invention,surfactants may be desirable since the inclusion of a surfactant mayhave the dual benefit of helping to maintain the active ingredient inuniform suspension in the gel formulation, while enhancing thebio-availability of the oxybutynin. Further, many surfactants also actas permeation enhancers. Surfactants suitable for use in the presentinvention may include, but are not limited to, lecithin; sorbitanmonoesters, such as sorbitan monooleate, sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monostearate; polysorbates, such as thoseprepared from lauric, palmitic, stearic and oleic acids (polysorbate 20and polysorbate 40); mononylphenyl ethers of polyethylene glycols, suchas the monoxynols (e.g. octoxynol and nonoxynol); polyoxyethylenemonoesters, such as polyoxeethylene monostearate, polyoxyethylenemonolaurate, polyoxyethylene monoleate; dioctyl sodium sulfosuccinate;sodium lauryl sulfate, sodium laurylate, sodium laurate,polyoxyethylene-sorbitan monolaurate; and polyoximers having a molecularweight between 2,000 and 8,000, poloxamer (182, 184, 231, 407); andmixtures thereof.

[0130] In another aspect of the present invention, additional suitablesolvents for use in the present invention may include, but are notlimited to, ethanol, glycerin, triethanolamine; ureas such asdiazolidinyl urea; anionic, cationic, amphoteric and nonionicsurfactants, including dialkyl sodium sulfosuccinate, polyoxyethyleneglycerol, polyethylene glycol glyceryl stearate, polyoxyethylene stearylether, propoxy-ethoxybutynincopolymer, polyoxyethylene fatty alcoholester, polyoxyethylene fatty acid ester, glycol salicylate, crotamiton,ethoxylated hydrogenated castor oil, butoxylated hydrogenated castoroil, limonene, peppermint oil, eucalyptus oil, cetyltrimethylammoniumbromide, benzalkonium chloride, and Tween (20, 40, 60, 80). In oneaspect of the present invention, a non-ionic surfactant may be used ifthe stability of oxidizable ingredients in the free form gel is affectedby the ionic strength of the formulation. In one aspect of the presentinvention, ethanol is used as the solvent. In another aspect of thepresent invention, glycerin is used as the solvent. In another aspect ofthe present invention, the solvent or surfactant may be present in anamount from about 30 wt % to about 100% of the free form gel. Thesurfactant or solvent may be present in an amount up to about 30% byweight of the free form gel.

[0131] In another aspect of the present invention, the free form gel maycontain up to about 10 wt % of a lipophilic or hydrophobic agent, whichmay serve as an emollient or anti-irritant, as an additional help inrelieving irritation, if any, caused by the oxybutynin or otherformulation components. Emollients suitable for use in the presentinvention may include lipophilic agents such as, but not limited to,fatty materials such as fatty alcohols of about 12 to 20 carbon atoms,fatty acid esters having about 12 to 20 carbon atoms in the fatty acidmoiety, petrolatum, mineral oils, and plant oils such as soybean oil,sesame oil, almond oil, aloe vera gel, glycerol, and allantoin. Inanother aspect of the present invention glycerol is used as theemollient.

[0132] In yet another detailed aspect of the present invention, otheradditives may be used in order to adjust the pH of the free form gel andthus reduce irritation and/or aid in obtaining proper gelling, pHadditives may be required such as, but not limited to, organic amines(e.g. methylamine, ethylamine, di/trialkylamines, alkanolamines,dialkanolamines, triethanolamine), carbonic acid, acetic acid, oxalicacid, citric acid, tartaric acid, succinic acid or phosphoric acid,sodium or potassium salts thereof, hydrochloric acid, sodium hydroxide,ammonium hydroxide and mixtures thereof.

[0133] Surprisingly, it has been discovered that in some embodiments,the specific pH of the formulation may enhance the permeation ofoxybutynin through the skin as compared to another pH. As a result, inone aspect of the present invention, the oxybutynin gel formulation mayhave a pH that enhances oxybutynin penetration through the skin ascompared to the penetration obtained at a different pH. In some aspects,the pH that aids in penetration enhancement may be a pH which is higherthan a pH that does not aid in penetration enhancement. In some aspects,the pH may be a basic pH. In other aspects, the pH may be a near neutralpH. In an additional aspect, the pH may be a pH substantially equivalentto the inherent pH of the specific type of oxybutynin used. In anotheraspect, the specific pH may provide a permeation enhancement that is atleast about 20% greater than the enhancement obtained at a different pH.Examples of specific formulations and pH therefore that enhanceoxybutynin permeation are contained below.

[0134] In yet another detailed aspect of the present invention,permeation enhancers may also be added to increase the rate ofpermeation of the active agent, such as oxybutynin, across the epidermallayer. Useful permeation enhancers allow desired drug delivery rates tobe achieved over a reasonably sized skin area, are non-toxic, causeminimal irritation, and are non-sensitizing. Although some of thesolvents mentioned above also act as permation enhancers other enhancerssuitable for use in the present invention include, but are not limitedto, triacetin, monoglycerides, glycerol monooleate, glycerolmonolaurate, glycerol monolineoleate, glycerol dioleate, glyceroltrioleate; fatty acid esters such as isopropyl myristate, isopropyladipate, methylpropionate and ethyl oleate; thioglycerol, calciumthioglycolate, lauric acid, myristic acid, strearic acid, oleic acid,oleyl alcohol, linoleic acid, palmitic acid, valeric acid, isopropanol,isobutanol, and mixtures thereof. In one aspect of the presentinvention, the enhancer is a monoglyceride. In another aspect of thepresent invention the enhancer is triacetin.

[0135] Additional enhancers suitable for use in the present inventionmay include, but are not limited to, N-methylpyrrolidone, N-dodecylpyrrolidone, hydroxypropyl-beta-cyclodextrin, lauryl alcohol, sulfoxidessuch as dimethylsulfoxide and decylmethylsulfoxide; ethers such asdiethylene glycol monoethyl ether and diethylene glycol monomethylether; 1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (see for example, U.S. Pat. Nos.3,989,816, 4,316,893, 4,405,616 and 4,557,934, each of which isincorporated herein by reference); alcohols such as ethanol, propanol,octanol, benzyl alcohol, and the like; amides and other nitrogenouscompounds such as urea, dimethylacetamide, dimethylformamide,2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; organic acids, such as salicylicacid and salicylates, citric acid and succinic acid; certain peptides,e.g., peptides having Pro-Leu at the N-terminus and followed by aprotective group (see for example, U.S. Pat. No. 5,534,496 which isincorporated herein by reference); and mixtures thereof.

[0136] In another aspect, the free form gels of the present inventionmay further contain about 0.05 to 2 weight % of a preservative,anti-microbial or anti-bacterial agent which prevents bacterial ormicrobial growth in the gel formulation. Preservatives suitable for usein the present invention may include, but are not limited to, sorbitol,p-oxybenzoic acid esters (e.g. methyl paraben, ethyl paraben, propylparaben, etc.), benzyl alcohol, chlorobutanol, betahydroxytoluene, andthimerosal. However, other conventional preservatives commonly used inpharmaceutical compositions will be readily recognized by those skilledin the art. In one aspect of the present invention, the preservative isa paraben.

[0137] In yet another aspect of the present invention, the free formgels may include an antioxidant. Suitable antioxidants for use in thepresent invention may include, but are not limited to,dl-alpha-tocopherol, d-alpha-tocopherol, d-alpha-tocopherol acetate,d-alpha-tocopherol acid succinate, dl-alpha-tocopherol acid succinate,dl-alpha-tocopherol palmitate, butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT), butylatedhydroxyquinone, ethyl gallate, propylgallate, octyl gallate, lauryl gallate, cephalm, ascorbic acid, ascorbyloleate, ascorbyl palmitate, sodium ascorbate, calcium ascorbate,hydroxycomarin, propylhydroxybenzoate, triliydroxybutylrophenone,dimethylphenol, diterlbulylphenol, vitamin E, lecithin and ethanolaminefor example. In one aspect of the present invention, the antioxidantcontains a tocopherol group. Other suitable antioxidants for oxybutyninwill be readily recognized by those skilled in the art.

[0138] In still another aspect of the present invention, lubricants maybe added to the free form gels of the present invention. Typicallubricants include magnesium stearate, calcium stearate, zinc stearate,magnesium oleate, magnesium palmitate, calcium palmitate, sodiumsuberate, potassium laurate, corn starch, potato starch, bentonite,citrus pulp, stearic acid, oleic acid, and palmitic acid.

[0139] In another aspect of the present invention, the topicalformulations described herein may also be prepared with liposomes,micelles, or microspheres. Liposoines are microscopic vesicles having alipid wall comprising a lipid bilayer. Liposomal preparations for use inthe present invention include cationic, anionic and neutralpreparations. Cationic liposomes suitable for use in the presentinvention may include, but are not limited to,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (LIPOFECTIN).Similarly, anionic and neutral liposomes may be used such asphosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline, dioleoylphosphatidyl glycerol, anddioleoylphoshatidyl ethanolamine. Methods for making liposomes usingthese and other materials are well known in the art.

[0140] In another detailed aspect of the present invention, micelles maybe prepared to deliver oxybutynin in accordance with the method of thepresent invention. Micelles suitable for use in the present invention,are comprised of surfactant molecules arranged such that the polar endsform an outer spherical shell, while the hydrophobic, hydrocarbon chainends are oriented towards the center of the sphere, forming a core.Surfactants useful for forming micelles for use in the present inventioninclude, but are not limited to, potassium laurate, sodium octanesulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodiumlauryl sulfate, docusate sodium, decyltrimethylammonium bromide,dodecyltrimethyl-ammonium bromide, tetradecyltrimethylammonium bromide,tetradecyltrimethyl-ammonium chloride, dodecylaminonium chloride,polyoxyl 8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10 andnonoxynol 30. Other methods for the preparation of micelles is known tothose skilled in the art.

[0141] In yet another aspect of the present invention, microspheres mayalso be incorporated into the present invention and encapsulate theoxybutynin and/or other components. Microspheres may be formed fromlipids, such as phospholipids and preparation of microspheres generallyis well known in the art.

[0142] Finally, in another aspect of the present invention, the vehiclesand formulations of the present invention may optionally contain minoramounts of such other commonly used cosmetic adjuvants or otheradditives such as dyes, perfumes, pacifiers, sunscreens, etc., as willbe readily recognized by those skilled in the art. In addition, it isalso contemplated that the free form gels of the present invention mayalso contain other components such as vitamins, lipids, hormones,additional active agents, or anti-inflammatory agents, such ascorticosteroids.

[0143] As will be appreciated by those skilled in the art, each specifictype of formulation may affect the rate of delivery and presentadditional variables in designing the composition of such a formulation.The addition of various components may also effect the drug deliveryproperties of the final topical formulation. Each component of thedelivery system may have independent effects or effects which occur incombination with another component and may vary depending on theparticular topical formulation used.

[0144] Several of the various components listed may serve more than onepurpose. Thus, although listed in one category, certain compounds mayhave recognized beneficial properties characteristic of anothercategory. The above categorization is provided merely to addorganization and is not meant to be a definitive classification of thecompounds listed. However, these general parameters are not limitationson the way in which the desired plasma levels may be achieved. Differentdelivery methods, rates, and amounts may be used to affect the desiredplasma levels by employing a formulation which produces differentparameters.

EXAMPLES

[0145] The following examples of non-oral delivery formulations having avariety of oxybutynin containing compositions are provided to promote amore clear understanding of the possible combinations of the presentinvention, and are in no way meant as a limitation thereon. Materialsused in the present invention were obtained from specific sources whichare provided as follows. Where the materials are available from avariety of commercial sources, no specific source has been provided.Oxybutynin free base was obtained from Ceres Chemical Co. Inc., WhitePlains, N.Y. (USA). The enantiomers of oxybutynin and namely, the (R)-and (S)-isomers were obtained from Sepracor. Sepracor, Marlborough,Mass. (USA).

Example 1 Preparation of Oxybutynin Adhesive Matrix Patch

[0146] The non-oral oxybutynin delivery devices used in the clinicalstudy referred to above were 13 and/or 39 cm² transdermal adhesivematrix patches. A general method of preparing transdermal adhesivematrix patches is described by U.S. Patent Nos. 5,227,169, and5,212,199, which are incorporated by reference in their entirety.Following this general method, the oxybutynin patches of this inventionwere prepared as follows:

[0147] Oxybutynin free base, triacetin (Eastman Chemical Co., Kingsport,N.Y.) and 87-2888 acrylic copolymer adhesives (National Starch andChemical Co., Bridgewater, N.J.) were mixed into a homogenous solutionand coated at 6 mg/cm² (dried weight) onto a silicone treated polyesterrelease liner (Rexham Release, Chicago, Ill.) using a two zonecoating/drying/laminating oven (Kraemer Koating, Lakewood, N.J.) toprovide a final oxybutynin adhesive matrix containing 15.4%, 9.0%, and75.6% by weight oxybutynin, triacetin and acrylic copolymer adhesive,respectively. A fifty micron thick polyethylene backing film (3M, St.Paul, Minn.) was subsequently laminated onto the dried adhesive surfaceof the oxybutynin containing adhesive matrix and the final laminatestructure was die cut to provide patches ranging in size from 13 cm² to39 cm² patches.

Example 2 Preparation of Oxybutynin Biodegradable Microsphere DepotInjection

[0148] Biodegradable microspheres for effecting a sustained-releasedepot injection may be used to deliver oxybutynin in accordance with themethod of the present invention. Microspheres were prepared by thefollowing method:

[0149] 12,000 molecular weight poly-d,l lactic acid (“PLA”, BirminghamPolymers, Birmingham, Ala.) was dissolved into methylene chloride at afinal concentration of 20% by weight. Oxybutynin free base was dissolvedinto the PLA solution at 4% by weight in the final solution. Awaterjacketed reaction vessel (temperature controlled at 5 degreesCelsius) equipped with a true-bore stirrer fitted with a Teflon turbineimpeller was charged with a de-ionized water containing 0.1% Tween 80.

[0150] The oxybutynin/PLA/methylene chloride solution was added dropwise into the reaction vessel and stirred to dispense the organicpolymer phase within the aqueous solution as fine particles. Theresultant suspension was filtered and washed once with de-ionized waterand finally dried on a roto-evaporator to removed methylene chloride.The resultant microspheres can be injected either intramuscularly orsubcutaneously to provide a prolonged systemic release of oxybutynin.

Example 3 Preparation of Topical Oxybutynin Formulation

[0151] Topically applied oxybutynin containing gel may be used todeliver oxybutynin in accordance with the method of the presentinvention. A general method of preparing a topical gel is known in theart. Following this general method, a topical gel comprising oxybutyninwas prepared as follows:

[0152] 95% ethanol (USP) was diluted with water (USP), glycerin (USP),and glycerol monooleate (Eastman Chemical, Kingsport N.Y.) to provide afinal solution at ethanol/water/glycerin/glycerol monooleate percentratios of 35/59/5/1, respectively. Oxybutynin free base was thendissolved into the above solution to a concentration of 10 mg/gram. Theresultant solution was then gelled with 1% hydroxypropyl cellulose(Aqualon, Wilmington, Del.) to provide a final oxybutynin gel. One totwo grams of the above gel is applied topically to approximately 200 cm²surface area on the chest, torso, and or arms to provide topicaladministration of oxybutynin.

Example 4 Clinical Study to the Determine the Pharmacokinetics ofOxybutynin, N-desethyloxybutynin, and Their Respective (R) and (S)Isomers Following Oral Administration of Racemic Oxybutynin inComparison to Transdermally Administered Racemic Oxybutynin

[0153] A clinical study in 16 healthy volunteers compared, in across-over fashion, the comparative plasma concentrations andpharmacokinetics of oxybutynin, N-desethyloxybutynin, and theirrespective (R)- and (S)-enantiomeric components.

[0154] Healthy volunteers were recruited from the local population andincluded men and women ranging in age from 19 to 45 years. Following apre-study examination to confirm a healthy condition in all volunteers,each subject participated in 2 study periods during which the testmedications, either a transdermal oxybutynin system applied for 4 daysor a single 5 mg oral immediate-release dose of oxybutynin, wereadministered. Blood samples were collected periodically throughout thestudy periods. Plasma was harvested from the samples according to astandard method. The quantities of (R) and (S) oxybutynin and (R) and(S) N-desethyloxybutynin were measured in the plasma samples through theapplication of a validated mass spectrometric method coupled with liquidchromatographic separation of the individual constituents. A PerkinElmer high performance liquid chromatographic pump was used inconjunction with a Chrom Tech AGP 150.2 chromatographic column. The massspectrometry instrument was an API 300 operated in MRM scan mode withelectrospray ionization. A linear response of the quantitation of theanalytes was confirmed with standard solutions and the performance ofthe assay was controlled using quality control samples analyzed inconjunction with the study samples. The range of linearity was 0.5 to 75ng/ml with linear correlation coefficients greater than 0.99 for allanalytes.

[0155]FIGS. 1, 2, 3, 6, and 7 show graphical displays of these data. InFIG. 1, oxybutynin and N-desethyloxybutynin plasma concentrations areshown following administration of the 5 mg immediate-release oral dosageoxybutynin hydrochloride tablets, Ditropan® Alza Corporation. Thesetablets were obtained commercially and can be obtained from variousgeneric manufacturers. Plasma concentration is indicated on the verticalaxis, and time is indicated on the horizontal axis. As can be seen, theplasma concentrations of N-desethyloxybutynin are significantly greaterthan oxybutynin plasma concentrations. The mean AUC ratio forN-desethyloxybutynin to oxybutynin is about 10:1.

[0156]FIG. 3 illustrates the plasma concentration profiles foroxybutynin and N-desethyloxybutynin during and following application ofthe transdermal system. As can be seen, the N-desethyloxybutynin plasmaconcentrations for the adhesive matrix patch embodiment, fall wellwithin the parameters prescribed by the present invention. The mean AUCratio for N-desethyloxybutynin to oxybutynin is about 0.9:1 and the meanplasma concentrations for N-desethyloxybutynin are less than about 2.5ng/ml.

[0157]FIGS. 6 and 7 illustrate the plasma concentrations of theindividual isomers of oxybutynin and N-desethyloxybutynin as measuredduring the clinical trial described above. As can be seen in FIG. 6,oral administration of oxybutynin leads to relatively highconcentrations of (R)-N-desethyloxybutynin. This active metabolitemoiety is present in the greatest concentration, and is several timesthe concentration of both (R) and (S) oxybutynin. The mean ratio of AUCof (R)-N-desethyloxybutynin to (R)-oxybutynin is about 17:1 and the meanAUC ratio of (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin isabout 1.5:1.

[0158] Following application of the transdermal oxybutynin system, themean AUC ratio of the active moieties, (R)-N-desethyloxybutynin to(R)-oxybutynin, is about 1:1, substantially lower than following oraladministration. Additionally, the mean AUC ratio of(R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is about 0.9:1,consistent with substantially lower metabolic first pass conversion ofthe active (R)-oxybutynin to (R)-N-desethyloxybutynin. The mean AUCratio of (R)- to (S)-oxybutynin is about 0.7:1, similar to that presentfollowing oral administration.

[0159] The lower overall amount of oxybutynin delivered duringtransdermal delivery of oxybutynin was estimated based on the residualamount of oxybutynin remaining in the transdermal system after the 4-dayapplication period subtracted from the amount determined in unusedtransdermal systems. The mean amount delivered over 4 days was about 12mg or an average of about 3 mg/day. The oral dose of oxybutyninadministered in the study was 5 mg, a dose that may be administeredevery 12 hours, or two times daily, during therapeutic use of theproduct. This allows a comparison of a dose of about 5 mg every 12 hoursfor oral treatment compared to about 1.5 mg every 12 hours fortransdermal treatment.

[0160] In summary, the pharmacokinetics of transdermal, non-oral,oxybutynin administration illustrate the aspects of the invention withregard to a sustained, slower rate of administration of oxybutynin and alower dose or overall amount of oxybutynin administered.

Example 5 Comparative Analysis of Therapeutic Efficacy and Incidence andSeverity of Anticholinergic Side Effects, Primarily Dry Mouth, ofConventional Oral Tablet Formulation and Transdermal Formulation of thePresent Invention

[0161] A clinical study of the efficacy and incidence of side effectswas conducted in 72 patients with overactive bladder. These patientswere recruited by independent clinical investigators located in variousregions of the U.S.A. Approximately half of the patients wereadministered oxybutynin hydrochloride in an immediate-release oraldosage formulation. The remaining patients were administered oxybutyninusing in each case one or more 13 cm² oxybutynin containing transdermaladhesive matrix patches. In each of these treatment groups, themedications were blinded by the concomitant administration of matchingplacebo forms of the treatments. In the case of active oral treatment,the patients applied placebo transdermal systems that contained allingredients of the active transdermal system with the exception of theactive drug oxybutynin. In like fashion, the active transdermaltreatment group received matching oral formulations without the activeoxybutynin constituent.

[0162] In this study, the patients included both men and women, with themajority being women with an average age of 63-64 years. All patientshad a history of urinary incontinence associated with overactive bladderand demonstrated a mean of at least 3 incontinent episodes per dayduring a washout period during which no medical therapy for incontinencewas used.

[0163] Therapeutic efficacy was based on the mean number of incontinentepisodes experienced per day as derived from a multiple-day patienturinary diary. The data are displayed graphically in FIG. 4.

[0164] As can be seen, the number of incontinent episodes for thoseindividuals treated by the non-oral method of the present invention isnearly identical to the number for those treated with the oralformulation. This indicates clearly that the present methods andcompositions provide for a therapeutically effective treatment forurinary incontinence and overactive bladder that is comparable to theconventional oral formulation, such as a 5 mg oral oxybutynin tablet.Incidence and/or severity of adverse drug experience was also comparedbetween the conventional oral tablet formulation of oxybutyninadministered as above and the transdermal formulation. Anticholinergicadverse experience, such as the incidence and severity of dry mouth, wasused as an indicator of the adverse experience that can be associatedwith the administration of either formulation and represents ananticholinergic side effect. The clinical study participants were askedto report this experience according to a standardized questionnaire. Thedata derived from the questionnaire are displayed graphically in FIG. 5.The percentage of participants reporting dry mouth is indicated on thevertical axis, and the severity of the dry mouth is indicated on thehorizontal axis.

[0165] As can be seen, only 6% of the participants who received the oralform reported no dry mouth effects. Conversely, 94% of theseparticipants reported experiencing some dry mouth. By contrast, 62% ofthe participants who were treated with the 13 cm² transdermal adhesivematrix patches reported no dry mouth effects. Therefore, only 38% ofthese participants reported experiencing some dry mouth. Therefore, theclinical data shows that matrix patch embodiment of the method of thepresent invention, provides a treatment for overactive bladder whichachieves nearly identical therapeutic effectiveness as an oral form,while significantly minimizing the incidence and or severity of adverseexperiences associated with oxybutynin administration.

[0166]FIG. 7 shows that the (R)-N-desethyloxybutynin concentrations arelower than the (S)-N-desethyloxybutynin concentrations, and further, theconcentrations of (R)-oxybutynin increase slowly and are maintained atan approximately constant level throughout the patch application timeperiod. The reduced plasma concentrations of (R)-N-desethyloxybutyninappears to have contributed to the minimization of the incidence andseverity of adverse drug experiences such as dry mouth, while the plasmaconcentrations of (R)-oxybutynin retain the therapeutic effectiveness ofthe treatment, as shown by FIGS. 4 and 5.

Example 6 Preparation of Free Form Oxybutynin Gel

[0167] A topically applied oxybutynin containing gel may be used todeliver oxybutynin in accordance with the method of the presentinvention. The gel of the present invention, and those described inExamples 9 through 11, were made by weighing glycerin (or otherhumectants and emollients) into a 6 oz jar, then pre-weighed water wasadded, followed by pre-weighed 2N sodium hydroxide (for oxybutyninchloride gel) or 2N hydrochloride (for oxybutynin free base gel). Thesodium hydroxide or sodium hydrochloride may be present at from 0 wt %to about 5 wt % of the total free form gel. Pre-weighed ethanol wasadded into a 6 oz jar. The active ingredient (either oxybutynin freebase or oxybutynin chloride) was weighed into a weighing dish on ananalytical balance then transferred into the 6 oz jar. After beingtightly capped, the jar was hand shaken until both the active ingredientand glycerin completely dissolved. Next, pre-weighed gelling agent wastransferred into the jar (agglomeration of the gelling agent can beavoided by slow dispersion of the gelling agent particles into the jar).The actual weights of each ingredient was determined by the differencein the transfer container weight. The jar was capped, wrapped withparafilm and put on a wrist shaker overnight to completely dissolve thegelling agent.

Example 7 Experimental Methods and In Vitro Flux Study for Free FormOxybutynin Gel

[0168] In vitro skin flux studies of Examples 9 through II wereconducted using full-thickness thickness skin samples (approximately 500μm) obtained from skin banks. The full-thickness skin samples werestored at −5° C. until experiments were conducted. The gender, age, sexand anatomical site information for each donor was recorded whenavailable.

[0169] The method used to apply a thin film of gel to the surface of theskin was adapted from Chia-Ming Chiang et al., Bioavailabilityassessment of topical delivery systems: in vitro delivery ofminoxidilfrom prototypical semi-solidformulations, IJP, 49:109-114,1989, which is incorporated herein by reference. The stratum corneumside of a piece of skin was attached to one side of an adhesive-coatedmetal shim having a circular hole of 0.64 cm² cut in the center. Theshim-membrane assembly was placed on top of a flat glass surface, andapproximately 15 μL of a formulation was dispensed into the centralcavity. With a microscope slide, the gel was spread across the surfaceof the skin, loading a dose of approximately 7 μL over the 0.64 cm²diffusional surface area. The applied dose was approximately 11 μL ofgel per cm² diffusional surface area, which is typical for topicalapplications.

[0170] The gel-loaded shim-membrane assembly was clamped between thedonor and receiver compartments of a modified Franz diffusion cell withthe dermal side facing the receiver solution. The receiver compartmentwas filled with 0.02% (w/v) NaN₃ to maintain sink conditions on thereceiver side throughout the duration of the experiment. The donorcompartment was unoccluded and open to the atmosphere. Cells were placedin a water bath heated with circulating water and calibrated to maintainthe skin surface temperature at (32±1)° C.

[0171] At predetermined time points, the entire contents of the receivercompartment was collected for quantifying the amount of drug, and thereceiver compartment refilled with fresh receptor medium, taking care toeliminate any air bubbles at the skin/solution interface. Each of thesamples were analyzed using high performance liquid chromatography(HPLC). The cumulative amount of drug permeated per unit area at anytime t (Qt,μg/cm²) was determined over a 24-hr period as follows:${Qt} = {\sum\limits_{n = 0}^{t}\frac{C_{n}V}{A}}$

[0172] where, C_(n) is the concentration (μg/mL) of the drug in thereceiver sample at the corresponding sample time, V is the volume offluid in the receiver chamber, and A is the diffusional area of the cell(0.64 cm²).

[0173] For the studies of Examples 8 through 10, typically fourreplicates were obtained per skin per system. A comparison of the meansof the values obtained for a given system from each skin indicateddifferences in permeation due to differences in skin.

Example 8 Topical Oxybutynin Free Base Gel Example 8.1

[0174] TABLE 1 Formulation^(a) Q_(t) (t = 24 hours) J_(ss) ET/E/G/D (%w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) 84.5/10/1.5/4 29.20 ± 20.24 1.22 ±0.84 80.5/10/1.5/8 44.92 ± 18.12 1.87 ± 0.76

[0175] These results show that an increase in permeation rate may beachieved by increasing the concentration of oxybutynin in theformulation. Thus, in one aspect of the invention, a method ofincreasing the oxybutynin flux rate by increasing the concentration ofoxybutynin in the formulation is provided.

Example 8.2

[0176] TABLE 2 Formulation^(a) Q_(t) (t = 24 hours) J_(ss) ET/W/G/D (%w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) 94.5/0/1.5/4.0 14.04 ± 9.47  0.56 ±0.39 74.5/20/1.5/4.0 19.11 ± 17.40 0.80 ± 0.73

[0177] These results show that acceptable flux rates can be achievedusing both aqueous and non-aqueous gel formulations. The results furthershow that flux rates may be increased by using an aqueous formulation.Thus, a method is provided for increasing the flux rate of an oxybutyninby increasing the water concentration contained in an oxybutynin gelformulation. In one aspect, the amount of water can be increased byabout 1% w/w to about 30% w/w. In another aspect, the amount of watercan be increased by about 5% w/w to about 25% w/w. In yet anotheraspect, the amount of water can be increased by about 10% w/w to about20% w/w. In one detailed aspect, the oxybutynin in the formulation maybean oxybutynin free base.

Example 8.3

[0178] TABLE 3 Formulation^(a) Q_(t) (t = 24 hours) J_(ss) EnhancerET/E/G/D (% w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) None 94.5/0/1.5/4.0 10.02± 5.38 0.42 ± 0.22 Triacetin 84.5/10.0/1.5/4.0 14.73 ± 6.70 0.61 ± 0.28

Example 8.4

[0179] TABLE 4 Formulation^(a) Q_(t) (t = 24 hours) J_(ss) pH of gelET/W/G/D (% w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) 6.0 74.5/20.0/1.5/4.015.90 ± 4.16 0.66 ± 0.17 9.8 74.5/20.0/1.5/4.0 20.71 ± 3.42 0.86 ± 0.14

[0180] Thus, a method is provided for increasing oxybutynin flux rate byincreasing the pH of the formulation. In one aspect, the formulation isa gel formulation and the pH is increased from about 4 to about 11. Inanother aspect, the pH is increased from about 5 to about 11. In yetanother aspect, the pH is increased from about 6 to about 11. In anotheraspect, the pH is increased from about 4 to about 10. In yet anotheraspect, the pH is increased from about 5 to about 10. In another aspect,the pH is increased from about 6 to about 10. In yet another aspect, thepH is increased from about 6 yo about 9. In one aspect, the pH of thegel formulation is about 6. In yet another aspect, the pH of the gelforinulation is about 9. It should be understood that the oxybutynin ispresent in either as its free base form, or its pharmaceuticallyacceptable salt (e.g., HCl) or a mixture thereof. In another aspect, theoxybutynin may be present as its R— or its S-isomer or itspharmaceutically acceptable salt or a mixture thereof. Moreover, theformulation may be prepared with or without a permeation enhancer. Thus,in one aspect, a method of increasing the oxybutynin flux rate from atopical formulation of oxybutynin by increasing the pH of theformulation which is substantially free of a permeation enhancer. Inanother aspect, a method of increasing the oxybutynin flux rate from atopical formulation of oxybutynin by increasing the pH of theformulation which may include a permeation enhancer. When theformulation comprises a permeation enhancer, the formulation may providean increased flux rate compared to a formulation that comprises anincreased pH but substantially free of an enhancer. In some aspects, theflux rate may be increased by at least two-fold. In some other aspects,the flux rates may be increased by 2-3 times, or even higher. In yetsome other aspects, the flux rate may be increased by 5-10 fold. Itshould also be understood that the increased flux rates due to increasedpH could be achieved with other topical formulations, such as creams,ointments, lotions, foams, sprays, and transdermal patches, and notnecessarily limited to the gel formulations. Example 8.5 TABLE 5Formulation^(a) Q_(t) (t = 24 hours) J_(ss) ET/W/Gl/G/D (% w/w)(μg/cm²/t)^(b) (μg/cm²/t)^(b) 74.0/20.0/0/2.0/4.0 13.26 ± 10.89 0.55 ±0.45 74.0/19.0/1.0/2.0/4.0 11.68 ± 10.63 0.49 ± 0.44

[0181] These results show that the incorporation of glycerin into thegel has no measurable impact on the skin permeation of oxybutynin.Therefore, glycerin can be used in a topical oxybutynin gel formulationin order to reduce skin irritation, or for other reasons as will berecognized by one of ordinary skill in the art.

Example 9 Topical Oxybutynin Chloride Gel Example 9.1

[0182] TABLE 6 Formulation^(a) Q_(t) (t = 24 hours) J_(ss) ET/W/G/D (%w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) 74.5/20.0/1.5/4.0 11.37 ± 3.94 0.47 ±0.16 69.5/25.0/1.5/4.0 10.99 ± 4.30 0.45 ± 0.14 64.5/30.0/1.5/4.0 10.02± 4.49 0.42 ± 0.19

[0183] These results show that a formulation comprising about 65% toabout 75% ethanol can be used effectively to delivery oxybutynin in atopical formulation. Example 9.2 TABLE 7 Formulation^(a) Q_(t) (t = 24hours) J_(ss) pH of gel ET/W/G/D/N (% w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b)6.0 74.5/18.7/1.5/4.0/1.3 18.94 ± 5.12 0.79 ± 0.21 4.674.5/20.0/1.5/4.0/0 13.18 ± 4.96 0.55 ± 0.21

[0184] These results show that oxybutynin chloride gel with pH 6.0produces higher oxybutynin skin permeation than that with pH 4.6.However, it is to be recognized that the formulation having a pH as lowas about 4.6 provides a desirable flux rate, in certain aspects.

Example 9.3

[0185] TABLE 9 Formulation^(a) Q_(t) (t = 24 hours) J_(ss) ET/W/Gl/G/D(% w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) 73.2/20.4/0/2.0/4.4 10.66 ± 6.170.44 ± 0.26 73.2/19.4/1.0/2.0/4.4 10.86 ± 8.62 0.45 ± 0.36

[0186] These results show that presence of glycerin in the oxybutyninchloride gel does not affect oxybutynin skin permeation through theskin. Therefore, glycerin can be included in an oxybutynin gelformulation as an emollient or other additive for reducing skinirritation or for other intended purposes that will be recognized bythose skilled in the art.

Example 10 Topical Oxybutynin Chloride and Free Base Gel

[0187] TABLE 9 Q_(t) (t = 24 Formulation^(a) hours) J_(ss) EnhancerEt/W/E/G/D₁/D₂ (% w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) None63.8/30.0/0/2.0/2.2/2.0 25.85 ± 15.35 1.08 ± 0.64 Triacetin58.8/30.0/5.0/2.0/2.2/2.0 41.77 ± 27.99 1.74 ± 1.17

[0188] These results show that triacetin significantly increases theskin flux of total oxybutynin as compared to the gel formulation withouttriacetin.

Example 11 Topical Oxybutynin Chloride Gel and Flux over Time Data

[0189] A free form oxybutynin chloride gel was prepared having acomposition of 73.3 wt % ethanol, 18.0 wt % water, 1.0 wt % glycerin,2.0 wt % KLUCEL HF, 4.4 wt % oxybutynin chloride, and 1.3 wt % sodiumhydroxide. The resulting gel had a pH of 6. Nine separate skin sampleswere tested for flux over a period of 48 hours and the results are shownin Table 10. After 24 hours of sampling, the remaining gel on the top ofthe skin was removed and then the 30 hour samples (6 hours after gelremoval) and 48 hour samples (24 hours after gel removal) were taken.TABLE 10 Sample Mean Cumulative Permeation Time 6 hr 24 hr 30 hr 48 hr 11.42 ± 2 01 4.57 ± 1.53  8.20 ± 0.40 11.95 ± 2 14  2 9.41 ± 0.58 19.61 ±6 71  31.82 ± 7 37 46 43 ± 8 72  3 4.59 ± 2 68 14 12 ± 7.17  16 15 ±9 81 24 77 ± 11 83 4 3.90 ± 1 23 9.40 ± 4 27 14.84 ± 6.70 26.47 ± 14 345 3.99 ± 3 28 16.17 ± 6 05  26.43 ± 7 89 38 35 ± 9.74  6 1.44 ± 0 433.70 ± 0.67  5.66 ± 1 06 8.75 ± 1.60 7 3.03 ± 0 45 7.39 ± 1 89 10.03 ±2 66 15 17 ± 4 25  8 6.62 ± 1 51 17.23 ± 3.24  27.27 ± 8 93 42 98 ±18.02 9 4.20 ± 0.95 13.73 ± 3.06  20.49 ± 4.52 32 19 ± 5.50  Mean 4.29 ±2.50 11.77 ± 5.72  17.84 ± 9.20 27.45 ± 13.65

[0190] In one aspect, an oxybutynin gel formulation for topicalapplication is provided that delivers oxybutynin at a mean flux rate offrom about 1.5 to about 7.0 ug/cm2/hr at about 6 hrs after application.In another aspect, an oxybutynin gel formulation for topical applicationis provided that delivers oxybutynin at a mean flux rate of from about 6to about 17 ug/cm2/hr at about 24 hrs after application. In yet anotheraspect, an oxybutynin gel formulation for topical application isprovided that delivers oxybutynin at a mean flux rate of from about 8 toabout 27 ug/cm2/hr at about 30 hrs after application. In yet anotheraspect, an oxybutynin gel formulation for topical application isprovided that delivers oxybutynin at a mean flux rate of from about 14to about 40 ug/cm2/hr at about 48 hrs after application. In anotheraspect, an oxybutynin gel formulation for topical application isprovided that delivers oxybutynin at a mean flux rate of from about 1.5to about 7.0 ug/cm2/hr at about 6 hrs after application; from about 6 toabout 17 ug/cm2/hr at about 24 hrs after application; from about 8 toabout 27 ug/cm2/hr at about 30 hrs after application; and from about 14to about 40 ug/cm2/hr at about 48 hrs after application. The oxybutynincan be present as a free base or as a pharmaceutially acceptable salt(e.g., such as HCl) or a mixture thereof. In yet another aspect, theoxybutynin can be present as its R-isomer or S-isomer, or theirpharmaceutically acceptable salts or mixtures thereof. When theoxybutynin is present as its corresponding isomer, in some aspects, themean flux rates for that isomer may be as following: from about 0.7 toabout 5.0 ug/cm2/hr at about 6 hrs after application; from about 3 toabout 9 ug/cm2/hr at about 24 hrs after application; from about 4 toabout 14 ug/cm2/hr at about 30 hrs after application; from about 6 toabout 25 ug/cm2/hr at about 48 hrs after application.

[0191] The above flux rates deliver therapeutic levels of oxybutynin toa subject in need thereof. Such therapeutic plasma levels may range fromabout 1.4 ng/ml to about 8 ng/ml, and in certain aspects, the plasmaconcentration may range from about 1.42 ng/ml to about 4 ng/ml. Inanother aspect, the plasma concentration may range from about 1.8 ng/mlto about 4 ng/ml. In yet another aspect, the plasma concentration mayrange from about 1.8 ng/ml to about 3 ng/ml.

Example 12 Topical Oxybutynin Cream

[0192] A free form oxybutynin cream containing the compositions in eachphase as shown in Table 11 may be produced. Oxybutynin is present in theformulation at from about 1 to about 10% w/w. TABLE 11 Phase Component %w/w Water Water 20-60  Propylene Glycol 1-10 Sodium Stearoyl Lactate0-5  20% PLURONIC 270 0-50 Methyl Paraben  0-0.5 Oil Oleic Acid 0-20Cetyl Alcohol 0-20 Glycerol Monooleate 0-10 Lauryl Acetate 0-10 PropylParaben  0-0.5

Example 13 Topical Oxybutynin Lotion

[0193] A free form oxybutynin lotion containing the compositions in eachphase as shown in Table 12 may be produced. Oxybutynin is present in theformulation at from about 1 to about 10% w/w. TABLE 12 Phase Component %w/w Water Water 20-90  Distearyl Dimonium 1-5  Chloride Sodium Chloride0-5  Methyl Paraben  0-0.5 Oil Glycerin 0-20 Petrolatum 0-10 IsopropylPalmitate 0-5  Cetyl Alcohol 0-10 Dimethicone 0-5  Propyl Paraben 0.0.5

Example 14 Topical Oxybutynin Emulsified Gel

[0194] A free form oxybutynin gel containing the compositions in eachphase as shown in Table 13 may be produced. Oxybutynin is present in theformulation at from about 1 to about 10% w/w. A free form oxybutynin gelmay be produced using an emulsified gel carrier. Oxybutynin is presentin the formulation from about 1 to about 20% w/w. Based on the forgoing,it is expected that the pH effects shown in the other applicableexamples can be observed in certain aspects of these formulations.Further, the emulsified gel bases are expected to deliver oxybutynineither in its free base form, in the form of a pharmaceuticallyacceptable salt, or in a mixture thereof, analogous to the above-recitedexamples, with delivery rates equivalent thereto. In addition, it is tobe understood that oxybutynin can be present in its R- or S-isomericforms. TABLE 13 Phase Component % w/w Water Water 30-90  PropyleneGlycol 1-10 Sodium Stearoyl Lactate 0-5  20% PLURONIC 270 0-20 SiliconeDioxide 0-1  Methyl Paraben  0-0.5 CARBOPOL 0.1-5   Oil Oleic Acid 0-10Cetyl Alcohol 0-10 Glycerol Monooleate 0-10 Lauryl Acetate 0-10 PropylParaben  0-0.5

Example 15 Topical Oxybutynin Ointment

[0195] A free form oxybutynin ointment containing the compositions ineach phase as shown in Table 14 may be produced. TABLE 14 Component %w/w Cholesterol 0-5 Stearyl Alcohol 0-5 White Wax  0-10 White Petrolatum 70-100 Oxybutynin  1-10

Example 16 Oxybutynin Free Form Gel Containing Optical Isomers

[0196] Table 15 shows the skin flux measured over a 24 hour period foreach of the R and S isomers in the chloride and free base forms. Bothoxybutynin free base and oxybutynin chloride are chiral molecules thatexists in two forms, R and S and were each tested in their opticallypure forms according to the present invention as shown in Table 15.TABLE 15 Q_(t) (t = 24 hours) (μg/cm²/t)^(b) Formulation^(a)Formulation^(a) Et/W/Gl/G/D₁/N (% w/w) Et/W/Gl/G/D₂/H (% w/w)73.2/17.9/1.0/2.0/4.4/1.5 73.2/18.3/1.0/2.0/4.0/1.5 R-Oxybutynin 6.98 ±4.26 7.08 ± 5.43 S-Oxybutynin 6.24 ± 3.77 6.87 ± 5.35

[0197] D₁=oxybutynin chloride; D₂=oxybutynin free base

[0198] N=2N sodium hydroxide (NaOH); H=2H Hydrochloride (HCl)

[0199]^(b)Mean±SD (n=3 skin donors)

[0200] These results show that the R and S isomers from both oxybutyninfree base gel and oxybutynin chloride gel permeate through the skin inequal amounts. Further, these results show that oxybutynin chloride canbe delivered at about the same rate as oxybutynin free base from atopically applied unoccluded gel.

[0201] It is to be understood that the above-described compositions andmodes of application are only illustrative of preferred embodiments ofthe present invention. Numerous modifications and alternativearrangements may be devised by those skilled in the art withoutdeparting from the spirit and scope of the present invention and theappended claims are intended to cover such modifications andarrangements.

[0202] Thus, while the present invention has been described above withparticularity and detail in connection with what is presently deemed tobe the most practical and preferred embodiments of the invention, itwill be apparent to those of ordinary skill in the art that numerousmodifications, including, but not limited to, variations in size,materials, shape, form, function and manner of operation, assembly anduse may be made without departing from the principles and concepts setforth herein.

What is claimed is:
 1. An oxybutynin gel formulation for topicalapplication comprising: a therapeutically effective amount ofoxybutynin; and a gel carrier, wherein the formulation has a pH of fromabout 4 to about 11 and wherein the oxybutynin is present as anoxybutynin free base, a pharmaceutically acceptable oxybutynin salt, ora mixture thereof, and wherein the formulation is prepared forunoccluded topical application to a skin surface.
 2. The oxybutynin gelformulation of claim 1, wherein the pH of the formulation is from about4 to about
 11. 3. The oxybutynin gel formulation of claim 1, wherein thepH of the formulation is from about 5 to about
 11. 4. The oxybutynin gelformulation of claim 1, wherein the pH of the formulation is from about6 to about
 11. 5. The oxybutynin gel formulation of claim 1, wherein thepH of the formulation is from about 4 to about
 10. 6. The oxybutynin gelformulation of claim 1, wherein the pH of the formulation is from about5 to about
 10. 7. The oxybutynin gel formulation of claim 1, wherein thepH of the formulation is from about 6 to about
 10. 8. The oxybutynin gelformulation of claim 1, wherein the pH of the formulation is about
 6. 9.The oxybutynin gel formulation of claim 1, wherein the pH of theformulation is about
 9. 10. The oxybutynin gel formulation of claim 1,wherein the oxybutynin is oxybutynin free base.
 11. The oxybutynin gelformulation of claim 1, wherein the oxybutynin is oxybutynin chloride.12. The oxybutynin gel formulation of claim 1, wherein the oxybutynin isa combination of oxybutynin free base and oxybutynin chloride.
 13. Anoxybutynin gel formulation for topical administration comprising: atherapeutically effective amount of oxybutynin in a gel carrier, whichupon unoccluded topical administration, is sufficient to provide anoxybutynin skin permeation rate of at least about 10 ug/cm² over aperiod of at least about 24 hours.
 14. The oxybutynin gel formulation ofclaim 13, wherein the skin permeation rate is at least about 20 ug/cm²over a period of at least about 24 hours.
 15. The oxybutynin gelformulation of claim 13, wherein the formulation has a pH that enhancesoxybutynin skin permeation upon unoccluded topical administration of theformulation to the skin.
 16. The oxybutynin gel formulation of claim 13,wherein the formulation includes a permeation enhancer.
 17. Theoxybutynin gel formulation of claim 13, wherein the oxybutynin isoxybutynin free base.
 18. The oxybutynin gel formulation of claim 13,wherein the oxybutynin is oxybutynin chloride.
 19. The oxybutynin gelformulation of claim 13, wherein the oxybutynin is a mixture ofoxybutynin free base and oxybutynin chloride.